Chronic carriers of hepatitis B virus (HBV) are at increased risk for hepatocellular carcinoma (HCC). Worldwide, however, the risk of HCC and other adverse outcomes varies substantially both between and within populations of HBV carriers. The reasons for these differences in the natural history of infection are not known. Our analysis of cohort studies in three endemic populations have suggested that the long term maintenance of high-titer viremia (i.e., equal to or > 1 pg/ml) is an important predictor of HCC. The mechanism behind the maintenance of viremia is, however, not well understood although it is clear that the host immune response plays a key role. In this application, we focus on molecular variants of the virus itself and polymorphisms of human immunoregulatory genes as potential predictive or explanatory factors in maintenance of viremia. We will draw upon established prospective cohorts of chronic HBV carriers in China, West Africa, and Asian- Americans. Our preliminary data support a relationship between deletions in the C ORF of HBV and clearance of active viral replication. In the proposed project we will test this hypothesis and extend our studies of molecular variation of HBV by application of novel statistical methods to sequence data. We will also test the hypothesis that maintenance of HBV viremia is associated with polymorphisms of the vitamin D receptor (VDR) and tumor necrosis factor alpha (TNFalpha) promoter. Allele frequencies for polymorphisms of lesser-studied immunomodulatory genes in our cohorts will be estimated in order to develop hypotheses about their relationship to maintenance of viremia in HBV carriers.